Abstract-The antifibrotic effects of the peptide hormone relaxin on cardiac and renal fibrosis were studied in 9-to 10-month-old male spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). Rats (nϭ8 to 9 per group) were allocated into 3 groups: WKY controls, vehicle-treated SHR (SHR-V), and relaxin-treated SHR (SHR-R). Relaxin (0.5 mg/kg per day) was administered via subcutaneously implanted osmotic mini-pumps over 2 weeks before hearts and kidneys were harvested for analysis. Collagen content was analyzed by hydroxyproline assay, gel electrophoresis, and quantitative histology. Zymography was used to determine matrix metalloproteinase (MMP) expression and Western blotting to determine proliferating cell nuclear antigen (PCNA) expression and ␣-smooth muscle actin (␣-SMA)/myofibroblast expression, whereas cardiac hypertrophy was assessed by myocyte size and real-time polymerase chain reaction of associated genes.

BackgroundCirculating microRNAs may represent novel markers for cardiovascular diseases. We evaluated whether circulating miRNAs served as potential biomarkers for diffuse myocardial fibrosis in patients with hypertrophic cardiomyopathy (HCM).MethodsCardiac magnetic resonance imaging with postcontrast T1 mapping was performed to non-invasively quantify diffuse myocardial fibrosis in HCM patients who were classified into two groups (T1 < 470 ms or T1 ≥ 470 ms, as likely or unlikely to have diffuse fibrosis, respectively). First, we screened 84 miRNAs using human serum/plasma miRNA array on plasma of 8 HCM patients (4/group based on T1 time) and 4 healthy controls. From the results of this initial array, 16 miRNAs were selected based on their fold changes and relevance to myocardial fibrosis for further validation by Taqman real-time PCR in 55 HCM patients.ResultsAmong the 16 miRNAs, the expression of miR-96-5p and miR-373-3p was low. The remaining 14 (miR-18a-5p, miR-146a-5p, miR-30d-5p, miR-17-5p, miR-200a-3p, miR-19b-3p, miR-21-5p, miR-193-5p, miR-10b-5p, miR-15a-5p, miR-192-5p, miR-296-5p, miR-29a-3p, and miR-133a-3p) were upregulated in HCM patients with T1 < 470 ms compared with those with T1 ≥ 470 ms, and 11 (except miR-192-5p, miR-296-5p and miR-133a-3p) were significantly inversely correlated with postcontrast T1 values. Individual miRNA had moderate diagnostic value for diffuse myocardial fibrosis (AUC: 0.663–0.742), but the diagnostic value was greatly improved (AUC: 0.87) for a combination of 8 miRNAs. In comparison, circulating markers of collagen turnover did not have predictive values for diffuse myocardial fibrosis.ConclusionsThese findings suggest that circulating miRNAs provide attractive candidates as putative biomarkers for diffuse myocardial fibrosis in HCM.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-015-0672-0) contains supplementary material, which is available to authorized users.

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Despite sustained pressure overload, inhibition of mTOR by a 4-week period of Rapamune treatment attenuates chronically established LVH and cardiac fibrosis with preserved contractile function.

As a prelude to investigating the mechanism of regression of pressure overload-induced left ventricular (LV) hypertrophy (LVH), we studied the time course for the development and subsequent regression of LVH as well as accompanying alterations in cardiac function, histology, and gene expression. Mice were subjected to aortic banding for 4 or 8 wk to establish LVH, and regression was initiated by release of aortic banding for 6 wk. Progressive increase in LV mass and gradual chamber dilatation and dysfunction occurred after aortic banding. LVH was also associated with myocyte enlargement, interstitial fibrosis, and enhanced expression of atrial natriuretic peptide, collagen I, collagen III, and matrix metalloproteinase-2 but suppressed expression of ␣-myosin heavy chain and sarcoplasmic reticulum Ca 2ϩ -ATPase. Aortic debanding completely or partially reversed LVH, chamber dilatation and dysfunction, myocyte size, interstitial fibrosis, and gene expression pattern, each with a distinct time course. The extent of LVH regression was dependent on the duration of pressure overload, evidenced by the fact that restoration of LV structure and function was complete in animals subjected to 4 wk of aortic banding but incomplete in animals subjected to 8 wk of aortic banding. In conclusion, LVH regression comprises a variety of morphological, functional, and genetic components that show distinct time courses. A longer period of pressure overload is associated with a slower rate of LVH regression. aortic banding; cardiac function/remodeling; model MYOCARDIAL HYPERTROPHY OCCURS in response to a variety of biomechanical stimuli. Although left ventricular (LV) hypertrophy (LVH) in response to increased afterload can be viewed as a compensatory mechanism to maintain cardiac output and normalize wall stress, LVH in the long term is an independent risk factor for a range of adverse consequences, such as myocardial ischemia, systolic and diastolic dysfunction, arrhythmias, and cardiac mortality (4, 9, 18, 19). Therefore, prevention or regression of LVH is a major therapeutic target whether achieved by pharmacological, mechanical, surgical, or genetic means (11,21,27,35,38). There has been clinical evidence that regression of LVH reduces morbidity and mortality and improves prognosis (9, 32). For example, antihypertensive treatment and aortic valvular replacement reverse LV structural, functional, and electrophysiological abnormalities (12,26,28). Similar benefits have also been observed after drug treatment in different animal models (3,30). Although reversal of LVH occurs after control of etiological factors, some studies have revealed incomplete reversal of pathophysiological changes, such as interstitial fibrosis, ventricular remodeling and dysfunction, and aberrant electrophysiology (2, 3, 12). Although numerous clinical and experimental studies have investigated effects of antihypertensive drugs (1, 3), coronary structure and function (17, 29), and alteration in gene expression (7, 31, 36) during reversal of LVH, the pathophys...

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Enhanced inotropy resulting from transgenic overexpression of alpha1A-AR is well maintained chronically after MI and limits echocardiography-determined LV remodeling, preserves function, and reduces acute heart failure death.

The pregnancy hormone relaxin has recently been shown to be cardio-protective. Despite its well-established antifibrotic actions in the heart, the effects of relaxin on cardiomyocytes (CM) remain to be determined. We investigated effects of isoform 2 of the human relaxin (H2-relaxin) on CM hypertrophy and apoptosis. In cultured neonatal rat CM, phenylephrine (50 microM) and cardiac fibroblast-conditioned medium were used respectively to induce CM hypertrophy. The degree of hypertrophy was indicated by increased cell size, protein synthesis and gene expression of atrial natriuretic peptide. Although H2-relaxin (16.7 nM) alone failed to suppress hypertrophy induced by phenylephrine, it repressed the cardiac fibroblast-conditioned medium-induced increase in protein synthesis by 24% (P<0.05) and reversed the increase in cell size (P<0.001) and atrial natriuretic peptide expression (P<0.01). We further studied the effect of H2-relaxin on CM apoptosis induced by H2O2 (200 microM). Studies of DNA laddering and nuclear staining demonstrated that H2-relaxin treatment reduced H2O2-induced DNA fragmentation. Real-time PCR and Western blot analysis revealed a significant increase in the Bcl2/Bax ratio in H2-relaxin-treated CM. Further analysis showed that activation of Akt (1.8-fold, P<0.001) and ERK (2.0-fold, P<0.01) were involved in the antiapoptotic action of H2-relaxin in CM, and that Gi/o coupling of relaxin receptors was associated with the H2-relaxin-induced Akt activation in CM. In conclusion, these results extend our current knowledge of the cardiac actions of relaxin by demonstrating that H2-relaxin indirectly inhibits CM hypertrophy and directly protects CM from apoptosis.